31 research outputs found

    Whole-exome sequencing as a tool for searching for genetic background modifiers in MEN1 patients with neuroendocrine pancreatic tumours, including insulinomas

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    Introduction: Multiple endocrine neoplasia type 1 (MEN1) is a monogenic disease caused by inactivating variants in the MEN1 gene. Although the reason for its development is well-known, disease phenotypes are unpredictable and differ even among carriers of the same pathogenic driver mutation. Genetic, epigenetic, and environmental factors may play a role in driving the individual phenotype. Those factors, however, still mostly remain unidentified. In our work, we focused on the inherited genetic background in pancreatic neuroendocrine neoplasms (pNENs) in MEN1 patients, and the pancreatic tumour subgroup with insulinoma. Material and methods: Whole exome sequencing was performed in MEN1 patients. The symptoms of interest were pancreatic neuroendocrine tumours in one analysis and insulinoma in the second. The study included families as well as unrelated cases. Genes with variants that are not neutral to the encoded gene product were defined in symptom-positive patients as compared to symptom-negative controls. The interpretation of the results was based on functional annotations and pathways shared between all patients with the given symptom in the course of MEN1. Results: Whole-exome screening of family members and unrelated patients with and without pNENs revealed a number of pathways that are common for all the analysed cases with pNENs. Those included pathways crucial for morphogenesis and development, proper insulin signalling, and structural cellular organization. An additional analysis of insulinoma pNEN patients revealed additional pathways engaged in glucose and lipid homeostasis, and several non-canonical insulin-regulating mechanisms. Conclusions: Our results show the existence of pathways that are identified in a non-literature-predefined manner, which might have a modifying function in MEN1, differentiating the specific clinical outcomes. Those results, although preliminary, provide evidence of the reasonableness of performing large-scale studies addressing the genetic background of MEN1 patients in determining their individual outcomes

    HindIII polymorphism of the lipoprotein lipase gene and blood pressure, anthropometric measurements, carotid artery structure and selected indices of the metabolism of glucose and lipids : family study

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    Wstęp Częstość zespołu metabolicznego, którego składową jest nadciśnienie tętnicze, wykazuje stały wzrost. Celem pracy była ocena w badaniu rodzin wpływu polimorfizmu HindIII genu lipazy lipoproteinowej (LPL, lipoprotein lipase) na ciśnienie tętnicze, otyłość, stężenie glukozy na czczo oraz profil lipidowy i grubość kompleksu błona wewnętrzna-błona środkowa (IMT, intima- media thickness) tętnic szyjnych. Materiał i metody Oznaczenia genetyczne polimorfizmu HindIII genu LPL wykonano u 326 osób, członków 86 rodzin nuklearnych, uczestników badania populacyjnego, prowadzonego w okolicach Krakowa. Z analizy wykluczono 15 osób chorych na cukrzycę. U pozostałych 311 uczestników wykonano pomiary ciśnienia tętniczego sfigmomanometrem rtęciowym, w domu pacjenta, podczas 2 oddzielnych wizyt, 5-krotnie w czasie każdej wizyty. Pomiary antropometryczne przeprowadzano według standardowego protokołu. Wykonano oznaczenia stężenia glukozy na czczo oraz profilu lipidowego. Za wskaźnik przebudowy naczyń tętniczych przyjęto IMT tętnic szyjnych w badaniu ultrasonograficznym. Wyniki Częstość genotypów wynosiła 55,0% dla +/+, 36,7% dla +/– oraz 8,3% dla –/– i nie wykazywała odchyleń od prawa Hardy’ego-Weinberga (p = 0,44). W pokoleniu rodziców (śr. wiek: 50,7 roku) osoby homozygotyczne –/– w porównaniu z nosicielami allelu (+) charakteryzowały się wyższym wskaźnikiem masy ciała (BMI) (31,6 vs. 28,0 kg/m2; p = 0,01) i podwyższonym stężeniem cholesterolu całkowitego (6,23 vs. 5,56 mmol/l; p = 0,05). Rodziców homozygotycznych wobec allelu (–) charakteryzowała również tendencja do wyższego stężenia cholesterolu frakcji LDL (3,92 vs. 3,29 mmol/l; p = 0,06) i większego IMT tętnic szyjnych (0,87 vs. 0,71 mm; p = 0,09). W pokoleniu potomków (śr. wiek: 24,1 roku) nosicielstwo allelu (–) wiązało się z wyższym stężeniem glukozy na czczo (4,48 vs. 4,12 mmol/l; p = 0,003), cholesterolu całkowitego (4,71 vs. 4,37 mmol/l; p = 0,01) i cholesterolu frakcji LDL (2,58 vs. 2,33 mmol/l; p = 0,04). W teście nierównowagi transmisji dla zmiennych ilościowych, polimorfizm HindIII genu LPL wpływał głównie na stężenie glukozy na czczo (c2 = 6,62, p = 0,01). Wnioski Polimorfizm HindIII genu lipazy lipoproteinowej wpływa na stężenie lipidów w surowicy krwi w obu grupach wiekowych oraz na stężenie glukozy na czczo w pokoleniu potomków. W pokoleniu rodziców jest także związany z otyłością oraz większą grubością kompleksu intima-media tętnic szyjnych.Background The prevalence of the metabolic syndrome, which includes essential hypertension, is continuously increasing. The aim of the study was to evaluate the influence of the lipoprotein lipase (LPL) gene HindIII polymorphism on blood pressure (BP), obesity, fasting glucose and lipoprotein profile, as well as carotid intima-media thickness (IMT) in the cohort of Polish families. Material and methods We genotyped 326 subjects, members of 86 nuclear families, enrolled in the populationbased study, for the HindIII polymorphism of the LLP gene. We excluded from this analysis 15 subjects with diabetes mellitus. Remaining 311 persons underwent conventional BP measurement during two separate home visits, 5 times on each visit. Anthropometric data were collected with standardized protocol. Peripheral blood was sampled in fasting subjects for routine biochemistry, including glucose and lipoprotein profile. Carotid IMT measured by carotid ultrasound was used as an index of atherosclerosis. Results Genotype frequencies were 55.0% for +/+, 36.7% for +/– and 8.3% for –/–, and did not deviate from the Hardy-Weinberg equilibrium (p = 0.44). Among parents (mean age: 50.7 years) –/– homozygotes as compared to (+) allele carriers showed increased body mass index (31.6 vs. 28.0 kg/m2; p = 0.01) and increased total cholesterol (6.23 vs. 5.56 mmol/l; p = 0.05). Parents homozygous for (–) allele presented also tendency towards higher levels of LDL cholesterol (3.92 vs. 3.29 mmol/l; p = 0.06) and carotid IMT (0.87 vs. 0.71 mm; p = 0.09). In offspring generation (mean age: 24.1 years), carrying of (–) allele resulted in higher fasting glucose (4.48 vs. 4.12 mmol/l; p = 0.003), total cholesterol (4.71 vs. 4.37 mmol/l; p = 0.01) and LDL cholesterol (2.58 vs. 2.33 mmol/l; p = 0.04). In quantitative transmission disequillibrium test, HindIII polymorphism of LPL mainly influenced fasting glucose levels (c2 = 6.62, p = 0.01). Conclusions HindIII polymorphism of the lipoprotein lipase gene influences lipids metabolism in both genera tions and in offspring generation also glucose metabolism. In parents generation, it is also related to obesity and increased carotid IMT

    How much of the predisposition to Hashimoto's thyroiditis can be explained based on previously reported associations?

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    Purpose Our insight in the genetics of Hashimoto’s thyroiditis (HT) has become clearer through information provided by genome-wide association studies and candidate gene studies, but remains still not fully understood. Our aim was to assess how many different genetic risk variants contribute to the development of HT. Methods 147 HT cases (10.2% men) and 147 controls (13.6% men) were qualified for the analysis. Intrinsic and environmental factors were controlled for. Polymorphisms (SNP) were chosen based on the literature and included markers of the genes PTPN22, CTLA4, TG, TPO among others, and of genomic regions pointed by GWAS studies. SNP were typed on a microarray. Variants in the HLA-DRB1 gene were identified by Sanger sequencing. Results Multivariate predisposition to HT was modeled. Based on the investigated group, a model of seven variables was obtained. The variability explained by this model was assessed at only 5.4821% (p = 2 × 10-6), which indicates that many dozens of factors are required simultaneously to explain HT predisposition. Conclusions We analyzed genetic regions commonly and most significantly associated with autoimmune thyroid disorders in the literature, on a carefully selected cohort. Our results indicated a lack of possibility to predict the risk of HT development, even with a multivariate model. We therefore conclude that strong associations of single genetic regions with HT should be interpreted with great caution. We believe that a change in the attitude towards genetic association analyses of HT predisposition is necessary. Studies including multiple factors simultaneously are needed to unravel the intricacies of genetic associations with HT

    Amiodarone and the thyroid

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    Lek antyarytmiczny — amiodaron, pochodna benzofuranu bogata w jod, wywołuje zaburzenia funkcji tarczycy w 15–20% przypadków. Amiodaron może powodować niedoczynność tarczycy (AIH) oraz nadczynność tarczycy (AIT). AIH jest leczona substytucyjnie lewotyroksyną, w jej przypadku nie jest konieczne odstawienie amiodaronu. Nadczynność tarczycy indukowaną amiodaronem dzielimy na dwa typy: typ 1 — nadczynność tarczycy związana z nadmierną produkcją hormonów tarczycowych, oraz typ 2, w której dominuje proces zapalenia tarczycy związanego z rozpadem gruczołu. Wyróżnia się również typ mieszany/nieokreślony, w którego patomechanizmie udział biorą oba powyżej opisane mechanizmy. Typ 1 AIT występuje zwykle na podłożu wcześniej występującej choroby tarczycy, zaś typ 2 w pierwotnie zdrowym gruczole tarczowym. Tionamidy są lekiem pierwszego rzutu w leczeniu typu 1 AIT, nadchloran sodowy/potasowy poprzez hamowanie wychwytu jodu może zwiększać odpowiedź na tionamidy. AIT typu 2 jest leczone głównie z zastosowaniem glikokortykosteroidów. Odpowiedź na leczenie zależy od wielkości gruczołu tarczowego i ciężkości tyreotoksykozy. Postaci mieszane mogą wymagać zastosowania złożonej terapii z użyciem tionamidów, nadchloranu sodowego/potasowego oraz steroidów. Leczenie radiojodem często jest niemożliwe z powodu zmniejszonego wychwytu jodu u pacjentów wcześniej leczonych amiodaronem. Zabieg usunięcia tarczycy jest bardzo pomocną formą leczenia nadczynności tarczycy indukowanej jodem, szczególnie w przypadkach opornych na leczenie farmakologiczne. Tyroidektomia wykonana przez doświadczony zespół chirurgów może być szczególnie pomocna u chorych z poważnymi zaburzeniami w układzie sercowo-naczyniowym. (Endokrynol Pol 2015; 66 (2): 176–196)Amiodarone, a benzofuranic iodine-rich antiarrhythmic drug, causes thyroid dysfunction in 15–20% of cases. Amiodarone can cause both hypothyroidism (AIH, amiodarone-induced hypothyroidism) and thyrotoxicosis (AIT, amiodarone-induced thyrotoxicosis). AIH is treated by L-thyroxin replacement and does not need amiodarone discontinuation. There are two main forms of AIT: type 1, a form of true iodineinduced hyperthyroidism; and type 2, a drug-induced destructive thyroiditis. However, mixed/indefinite forms exist, contributed to by both pathogenic mechanisms. Type 1 AIT usually occurs in diseased thyroid glands, whereas type 2 AIT develops in substantially normal thyroid glands. Thioamides represent the first-line treatment for type 1 AIT, but iodine-replete glands are poorly responsive; sodium/potassium perchlorate, by inhibiting thyroidal iodine uptake, may increase the response to thioamides. Type 2 AIT is best treated by oral glucocorticoids. Response depends on thyroid volume and severity of thyrotoxicosis. Mixed/indefinite forms may require a combination of thioamides, potassium perchlorate, and steroids. Radioiodine treatment is usually not feasible because amiodarone-related iodine load decreases thyroidal radioiodine uptake. Thyroidectomy represents an important and helpful option in cases resistant to medical therapy. Surgery performed by a skilled surgeon may represent an emergent treatment in patients who have severe cardiac dysfunction. (Endokrynol Pol 2015; 66 (2): 176–196

    Glucagon-like peptide-1 receptor imaging with [Lys^{40}(Ahx-HYNIC-^{99m}Tc/EDDA)NH_2]-Exendin-4 for the diagnosis of recurrence or dissemination of medullary thyroid cancer : a preliminary report

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    Introduction. Epidemiological studies on medullary thyroid cancer (MTC) have shown that neither a change in stage at diagnosis nor improvement in survival has occurred during the past 30 years. In patients with detectable serum calcitonin and no clinically apparent disease, a careful search for local recurrence, and nodal or distant metastases, should be performed. Conventional imaging modalities will not show any disease until basal serum calcitonin is at least 150 pg/mL. The objective of the study was to present the first experience with labelled glucagon-like peptide-1 (GLP-1) analogue [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 in the visualisation of MTC in humans. Material and Method. Four patients aged 22–74 years (two with sporadic and two with MEN2 syndrome-related disseminated MTC) were enrolled in the study. In all patients, GLP-1 receptor imaging was performed. Results. High-quality images were obtained in all patients. All previously known MTC lesions have been confirmed in GLP-1 scintigraphy. Moreover, one additional liver lesion was detected in sporadic MTC male patient. Conclusions. GLP-1 receptor imaging with [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 is able to detect MTC lesions. GLP-1 scintigraphy can serve as a confirmatory test in MTC patients, in whom other imaging procedures are inconsistent

    Efficacy and safety of 90Y-DOTATATE therapy in neuroendocrine tumours

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    Wstęp: Celem pracy była ocena skuteczności oraz toksyczności celowanej terapii receptorowej (PRRT) guzów neuroendokrynnych z wykorzystaniem analogu somatostatyny Tyr3-octreotate znakowanego 90Y (90Y-DOTATATE). Materiał i metody: Do badania włączono 46 pacjentów z rozsianym lub nieoperacyjnym guzem NET. 90Y-DOTATATE podawano w 3–5 kursach w odstępach 4–9-tygodniowych. Każdorazowo wyznaczano aktywność terapeutyczną, uwzględniając taką całkowitą powierzchnię ciała, by nie przekroczyć sumarycznej wartości 7,4 GBq/m2. Przed terapią i po niej wykonano oznaczenia parametrów morfotycznych, nerkowych oraz wątrobowych, a także stężenia chromograniny A. Wyniki: Spośród 46 leczonych pacjentów jeden chory zmarł przed zakończeniem pełnego cyklu terapeutycznego, a 16 po zakończeniu terapii, w tym jeden z powodu zawału serca. W 12. miesiącu obserwacji stwierdzono 47% stabilizacji, 31% częściowych odpowiedzi oraz 9% progresji wśród 45 pacjentów, którzy ukończyli leczenie. Pięciu chorych zmarło przed 12. miesiącem obserwacji. W jednym przypadku utracono możliwość uzyskania informacji o chorym po 12 miesiącach. Okres czasu bez progresji choroby wyniósł 37,4 miesiąca. W ciągu pierwszego roku od zakończenia terapii zaobserwowano jedynie przejściowe obniżenie wartości morfotycznych krwi oraz przejściowy wzrost stężenia kreatyniny i spadek wartości przesączania kłębuszkowego (GFR). Wnioski: Celowana terapia receptorowa z użyciem 90Y-DOTATATE może być skuteczną oraz stosunkowo bezpieczną metodą leczenia prowadzącą do częściowej odpowiedzi lub stabilizacji choroby u większości pacjentów. (Endokrynol Pol 2011; 62 (5): 392–400)Background: The aim of this study was to assess the efficacy and toxicity of peptide receptor radionuclide therapy (PRRT) with the use of the high affinity somatostatin receptor subtype 2 analogue, 90Y labelled Tyr3-octreotate, (90Y-DOTATATE) in neuroendocrine tumours (NETs). Material and methods: 46 patients with disseminated or non-operable NET were enrolled in this study. The 90Y-DOTATATE therapeutic activity was calculated per total body surface area up to a total of 7.4 GBq/m2 administered in three to five cycles, repeated every four to nine weeks. Before and after the therapy, blood tests for haematology, kidney and liver function, and chromogranin A were performed. Results: Out of 46 90Y-DOTATATE treated patients, one died before completing the therapy and 16 died after completing the therapy, among them one due to myocardial infarction. After 12 month follow-up, stabilisation of disease was observed in 47%, partial remission in 31%, and progression in 9% of the 45 patients who completed the therapy. Five patients died before completion of 12 months of follow-up. One of the patients died due to myocardial infarction. In one case, the information after 12 months is incomplete. The progression free survival was 37.4 months. During 12 months follow-up, transient decrease of PLT, WBC and haemoglobin values was observed. A transient increase of creatinine level (within normal ranges) and decrease of GFR values were found. Conclusions: NETs 90Y-DOTATATE therapy results in symptomatic relief and tumour mass reduction. The mild critical organ toxicity does not limit the PRRT of NETs. (Pol J Endocrinol 2011; 62 (5): 392–400

    Glucagon-like peptide-1 receptor imaging with [Lys^{40}(Ahx-HYNIC-^{99m}Tc/EDDA)NH_2]-exendin-4 for the detection of insulinoma

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    PURPOSE: The objective of this article is to present a new method for the diagnosis of insulinoma with the use of [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4. METHODS: Studies were performed in 11 patients with negative results of all available non-isotopic diagnostic methods (8 with symptoms of insulinoma, 2 with malignant insulinoma and 1 with nesidioblastosis). In all patients glucagon-like peptide-1 (GLP-1) receptor imaging (whole-body and single photon emission computed tomography/CT examinations) after the injection of 740 MBq of the tracer was performed. RESULTS: Both sensitivity and specificity of GLP-1 receptor imaging were assessed to be 100 % in patients with benign insulinoma. In all eight cases with suspicion of insulinoma a focal uptake in the pancreas was found. In six patients surgical excision of the tumour was performed (type G1 tumours were confirmed histopathologically). In one patient surgical treatment is planned. One patient was disqualified from surgery. In one case with malignant insulinoma pathological accumulation of the tracer was found only in the region of local recurrence. The GLP-1 study was negative in the other malignant insulinoma patient. In one case with suspicion of nesidioblastosis, a focal accumulation of the tracer was observed and histopathology revealed coexistence of insulinoma and nesidioblastosis. CONCLUSION: [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4 seems to be a promising diagnostic tool in the localization of small insulinoma tumours, but requires verification in a larger series of patients

    ^{99m}Tc labeled glucagon-like peptide-1-analogue (^{99m}Tc-GLP1) scintigraphy in the management of patients with occult insulinoma

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    INTRODUCTION: The aim of this study was to assess the utility of [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH(2)]-exendin-4 scintigraphy in the management of patients with hypoglycemia, particularly in the detection of occult insulinoma. MATERIALS AND METHODS: Forty patients with hypoglycemia and increased/confusing results of serum insulin and C-peptide concentration and negative/inconclusive results of other imaging examinations were enrolled in the study. In all patients GLP-1 receptor imaging was performed to localise potential pancreatic lesions. RESULTS: Positive results of GLP-1 scintigraphy were observed in 28 patients. In 18 patients postsurgical histopathological examination confirmed diagnosis of insulinoma. Two patients had contraindications to the surgery, one patient did not want to be operated. One patient, who presented with postprandial hypoglycemia, with positive result of GLP-1 imaging was not qualified for surgery and is in the observational group. Eight patients were lost for follow up, among them 6 patients with positive GLP-1 scintigraphy result. One patient with negative scintigraphy was diagnosed with malignant insulinoma. In two patients with negative scintigraphy Munchausen syndrome was diagnosed (patients were taking insulin). Other seven patients with negative results of (99m)TcGLP-1 scintigraphy and postprandial hypoglycemia with C-peptide and insulin levels within the limits of normal ranges are in the observational group. We would like to mention that (99m)Tc-GLP1-SPECT/CT was also performed in 3 pts with nesidioblastosis (revealing diffuse tracer uptake in two and a focal lesion in one case) and in two patients with malignant insulinoma (with the a focal uptake in the localization of a removed pancreatic headin one case and negative GLP-1 1 scintigraphy in the other patient). CONCLUSIONS: (99m)Tc-GLP1-SPECT/CT could be helpful examination in the management of patients with hypoglycemia enabling proper localization of the pancreatic lesion and effective surgical treatment. This imaging technique may eliminate the need to perform invasive procedures in case of occult insulinoma
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